1. Technical Field
This invention relates to novel pyridazine derivatives, which have excellent inhibitory activity against interleukin-1xcex2 production and are useful for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases and the like, and also to medicines containing them as effective ingredients.
2. Background Art
In many diseases, for example, rheumatism, arthritis, osteoporosis, inflammatory colitis, immune deficiency syndrome, ichorrhemia, hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson""s disease, Alzheimer""s disease, leukemia and the like, stimulation of interleukin-1xcex2 production, an inflammatory cytokine, is observed. This interleukin-1xcex2 serves to induce synthesis of an enzyme which is considered to take part in inflammation like collagenase and PLA2 and, when intra-articularly injected to animals, causes multi-articular destruction highly resembling rheumatoid arthritis. On the other hand, interleukin-1xcex2 is controlled in activity by interleukin-1xcex2 receptor, soluble interleukin-1 receptor and interleukin-1 receptor antagonist.
From research conducted making use of recombinants of these bioactivity-inhibiting substances, anti-interleukin-1xcex2 antibodies and anti-receptor antibodies against various disease models, interleukin-1xcex2 has been found to play an important role in the body, leading to an increasing potential of substances having interleukin-1xcex2 inhibitory activity as therapeutics for such diseases.
For example, immunosuppressors and steroids which are used for the treatment of rheumatism out of such many diseases have been reported to inhibit the production of interleukin-1xcex2. Even among medicaments currently under development, KE298, a benzoylpropionic acid derivative [The Japanese Society of Inflammation (11th), 1990], for example, has been reported to have inhibitory activity against interleukin-1xcex2 production although it is an immunoregulator. Inhibitory activity against interleukin-1xcex2 production is also observed on a group of compounds which are called xe2x80x9cCOX-2 selective inhibitorsxe2x80x9d, for example, nimesulide as a phenoxysulfonanilide derivative (DE 2333643), T-614 as a phenoxybenzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap (hydroxyindole derivative) as a dual inhibitor (COX-1/5-LO).
For all of these compounds, however, interleukin-1xcex2 production inhibitory activity is not their primary action so that their inhibitory activity against interleukin-1xcex2 production is lower than their primary action.
In recent years, increasingly active research is under way for the synthesis of compounds with a focus placed on inhibitory activity against interleukin-1xcex2 production. Production inhibitors synthesized in such research can be classified into a group of compounds which inhibit the transfer process of an inflammatory signal to a cell nucleus and another group of compounds which inhibit an enzyme ICE that functions in the processing of a precursor of interleukin-1xcex2. Known examples of compounds presumed to have the former action include SB203580 [Japanese Language Laid-Open (Kokai) Publication (PCT) No. HEI 7-503017], FR167653 (Eur. J. Pharm., 327, 169-175, 1997), E-5090 (EP 376288), CGP47969A (Gastroenterology, 109, 812-828, 1995), hydroxyindole derivatives (Eur. J. Med. Chem. 31, 187-198, 1996), and triarylpyrrole derivatives (WO 97/05878), while known examples of compounds presumed to have the latter action include VE-13,045 which is a peptide compound (Cytokine, 8(5), 377-386, 1996).
None of these compounds can however exhibit sufficient inhibitory activity against interleukin-1xcex2 production.
On the other hand, a variety of 5,6-diphenylpyridazine derivatives are known to have analgesic and anti-inflammatory action (EUR. J. MED. CHEM., 14, 53-60, 1979). Absolutely nothing has however been known with respect to inhibitory activity against interleukin-1xcex2 production by these 5,6-diphenylpyridazine derivatives.
Accordingly, an object of the present invention is to provide a compound having excellent inhibitory activity against interleukin-1xcex2 production and also a medicine containing it as an effective ingredient.
Under such circumstances, the present inventors have proceeded with an extensive investigation. As a result, it has been found that pyridazine derivatives represented by the below-described formula (1) have excellent inhibitory activity against interleukin-1xcex2 production and are useful as medicines for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases and the like, leading to the completion of the present invention.
Namely, the present invention provides a pyridazine derivative represented by the following formula (1): 
wherein R1 represents a substituted or unsubstituted aryl group, R2 is a phenyl group substituted at least at 4-position by a lower alkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, and optionally has one or more substituents at the remaining positions, R3 represents a hydrogen atom, a lower alkoxyl group, a halogenated lower alkyl group, a lower cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted, nitrogen-containing heterocyclic ring residue, a substituted or unsubstituted aminocarbonyl group, or a lower alkylcarbonyl group, A represents a single bond or a linear or branched lower alkylene group or lower alkenylene group, X represents an oxygen atom or a sulfur atom, and the dashed line indicates that the carbon-carbon bond between the 4-position and the 5-position is a single bond or a double bond, with the proviso that A is a single bond when R3 is a halogenated lower alkyl group and that the following combinations are excluded: R1 and R2 are 4-methoxyphenyl groups, X is an oxygen atom, the carbon-carbon bond at the 4-position and the 5-position is a double bond, A is a single bond, and R3 is a hydrogen atom or a 2-chloroethyl group; or a salt thereof.
Further, the present invention also provides a medicine comprising the pyridazine derivative (1) or the salt thereof as an effective ingredient.
Furthermore, the present invention also provides a pharmaceutical composition comprising the pyridazine derivative (1) or the salt thereof and a pharmaceutically acceptable carrier.
Moreover, the present invention also provides use of the pyridazine derivative (1) or the salt thereof as a medicine.
In addition, the present invention also provides a method for treating a disease caused by stimulation of interleukin-1xcex2 production, which comprises administering the pyridazine derivative (1) or the salt thereof.
As will be demonstrated in tests to be described subsequently herein, the inhibitory activity against interleukin-1xcex2 production by the pyridazine derivative (1) or the salt thereof is extremely strong and reaches 100 to 1,000 times as high as the action of the abovedescribed known 5,6-diphenylpyridazine derivatives (EUR. J. MED. CHEM. 14, 53-60, 1979).
The pyridazine derivative according to the present invention is represented by the formula (1). In the formula, illustrative of the aryl group represented by R1 can be phenyl, naphthyl and pyridyl, with phenyl and pyridyl being particularly preferred. These aryl groups may contain 1 to 3 substituents. Examples of such substituents can include halogen atoms, lower alkyl groups, lower alkoxyl groups, lower alkylthio groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups, carboxyl group, lower alkoxycarbonyl groups, nitro group, amino group, and lower alkylamino groups. Here, illustrative of the halogen atoms can be fluorine, chlorine, bromine and iodine. The lower alkyl groups are those containing 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl and n-butyl. Illustrative of the lower alkoxyl groups can be those containing 1 to 6 carbon atoms, for example, methoxy, ethoxy and propoxy. Illustrative of the lower alkylthio groups can be those containing 1 to 6 carbon atoms, for example, methylthio, ethylthio and propylthio. Illustrative of the lower alkylsulfinyl groups can be those containing 1 to 6 carbon atoms, for example, methylsulfinyl, ethylsulfinyl and propylsulfinyl. Illustrative of the lower alkylsulfonyl groups can be those containing 1 to 6 carbon atoms, for example, methylsulfonyl, ethylsulfonyl and propylsulfonyl. Illustrative of the lower alkoxycarbonyl groups can be those having alkoxyl groups each of which contains 1 to 6 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl. Illustrative of the lower alkylamino groups can be those having one or two alkyl groups each of which contains 1 to 6 carbon atoms, for example, methylamino, dimethylamino, ethylamino and propylamino. The lower alkyl moieties in these substituents may be linear, branched or cyclic.
Preferred as R1 is a phenyl or pyridyl group, which may be substituted by 1 to 3 substituents selected from halogen atoms and lower alkoxyl groups, these substituents being preferably present at 3-, 4- or 5-position.
Preferred as R2 is a phenyl group, which may be substituted at 4-position by a lower alkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, and at the other position by 1 or 2 substituents selected from halogen atoms, lower alkoxyl groups, lower alkylthio groups, lower alkylsulfinyl groups and lower alkylsulfonyl groups. Examples of the halogen atom, lower alkoxyl group, lower alkylthio group, lower alkylsulfinyl group and lower alkylsulfonyl group as the substituents on the phenyl group as R2 include the same groups as those recited as R1. These substituents are preferably positioned at only 4-position, at 3- or 4-position, or at any of 3-, 4- or 5-position.
Illustrative of the lower alkoxyl group and the substituted or unsubstituted aryl group out of those represented by R3 can be similar to those exemplified above in connection with R1.
Illustrative of the halogenated lower alkyl group can be lower alkyl groups substituted by one or more halogen atoms as exemplified above in connection with R1.
Examples of the lower cycloalkyl group can include those having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Illustrative of the aryloxy group can be a phenyloxy group, which may contain similar substituent or substituents as in the case of R1.
Illustrative of the nitrogen-containing heterocyclic ring residue can be saturated, nitrogen-containing heterocyclic ring residue such as piperidino, piperidyl, piperazino and morpholino; and nitrogen-containing aromatic heterocyclic ring residue such as pyridyl. These residue may contain similar substituents as in the case of R1. Further, each of them may additionally contain one or more carbonyl groups bonded thereto.
The aminocarbonyl group may contain similar substituents as in the case of R1 and also aralkyl groups such as benzyl and phenethyl.
Illustrative of the lower alkylcarbonyl group can be those containing 1 to 6 carbon atoms, for example, methylcarbonyl and ethylcarbonyl.
Preferred examples of R3 can include a hydrogen atom; lower alkoxyl groups; halogenated lower alkyl groups; lower cycloalkyl groups; phenyl, pyridyl and phenyloxy groups each of which may be substituted by 1 to 3 substituents selected from halogen atoms, lower alkyl groups, lower alkoxyl groups, carboxyl group, lower alkoxycarbonyl groups, nitro group, amino group, lower alkylamino groups and lower alkylthio groups; substituted or unsubstituted piperidino, piperidyl, piperazino and morpholino groups; and substituted or unsubstituted aminocarbonyl groups; and lower alkylcarbonyl groups.
Among those represented by A, the lower alkylene group can be a linear or branched one having 1 to 6 carbon atoms, examples of which can include methylene, ethylene and trimethylene. The lower alkenylene group can be a linear or branched one having 2 to 9 carbon atoms, with one having 2 to 6 carbon atoms and 1 to 3 double bonds being preferred. Illustrative can be ethenylene, propenylene, butenylene and butadienylene.
Preferred examples of A can be linear or branched lower alkylene groups having 1 to 6 carbon atoms and linear or branched, lower alkenylene groups having 2 to 9 carbon atoms.
Preferred examples of the pyridazine derivative (1) can include those containing, as R1, a phenyl or pyridyl group substituted by 1 to 3 substituents selected from halogen atoms and lower alkoxy groups; as R2, a phenyl group, which may be substituted at 4-position by a lower alkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, and at the other position by 1 or 2 substituents selected from halogen atoms, lower alkoxyl groups, lower alkylthio groups, lower alkylsulfinyl groups and lower alkylsulfonyl groups; as R3, a hydrogen atom, a lower alkoxyl group, a halogenated lower alkyl group, a lower cycloalkyl group, or a phenyl, pyridyl or phenyloxy group which may be substituted by 1 to 3 substituents selected from halogen atoms, lower alkyl groups, lower alkoxyl groups, carboxyl group, lower alkoxycarbonyl groups, nitro group, amino group, lower alkylamino groups and lower alkylthio groups, a substituted or unsubstituted piperidino, piperidyl, piperazino or morpholino group, a substituted or unsubstituted aminocarbonyl group, or a lower alkylcarbonyl group; and as A, a linear or branched lower alkylene group having 1 to 6 carbon atoms or a linear or branched lower alkenylene group having 2 to 9 carbon atoms.
In the present invention, compounds represented by the following formula (1A) are also preferred: 
wherein R4 represents a linear or branched lower alkyl or lower alkenyl group, a lower cycloalkyl group or a lower cycloalkylmethyl group, and X represents an oxygen atom or a sulfur atom.
In the formula (1A), examples of the lower alkyl group out of those represented by R4 can include linear or branched lower alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and n-hexyl. Examples of the lower alkenyl group can include linear or branched lower alkenyl groups having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms and 1 to 2 double bonds, for example, ethenyl, propenyl, butenyl, isobutenyl and butadienyl. Examples of the lower cycloalkyl group can include those having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Illustrative of the lower cycloalkyl group in the lower cycloalkyl methyl group can be those exemplified above.
Particularly preferred examples of R4 can include alkyl groups having 1 to 4 carbon atoms, alkenyl groups having 2 to 4 carbon atoms, cycloalkyl groups having 3 to 6 carbon atoms, and cycloalkylmethyl groups.
Preferred examples of the pyridazine derivative (1) can include 5,6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one, 2-allyl-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-cyclopropyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazine-3-thione, 5,6-bis(4-methoxyphenyl)-2-cyclopentyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-cyclopentylmethyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazin-3-one, 5-(4-chlorophenyl)-6-(4-methylthiophenyl)-2-benzyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazine-3-thione, and 5,6-bis(3-fluoro-4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one.
No particular limitation is imposed on the salt of the pyridazine (1), said salt also pertaining to the present invention, insofar as it is a pharmacologically acceptable salt. Illustrative can be acid addition salts of mineral acids, such as the hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate; and acid addition salts of organic acids, such as the benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate and citrate.
Further, the compounds according to the present invention may exist in the form of solvates represented by hydrates and also in the form of keto-enol tautomers. Such solvates and isomers should also be encompassed by the present invention.
The pyridazine derivatives (1) according to the present invention can be prepared, for example, by the following processes. 
wherein R5 represents a lower alkyl group, and R1, R2, R3 and A have the same meanings as defined above.
A description will be made specifically about respective preparation processes of compounds (1a), (1b), (1c), (1d) and (1e) among the pyridazine derivatives (1).
(1) Preparation of 4,5-dihydro-2H-pyridazin-3-one derivatives (1a: in the formula (1), A is a single bond, R3 is a hydrogen atom, X is an oxygen atom, and a single bond is formed between the 4-position and the 5-position):
A 4,5-dihydro-2H-pyridazin-3-one derivative (1a) can be obtained by reacting a haloacetate ester with a 2-arylacetophenone derivative (2) and then reacting hydrazine hydrate with the resultant product.
The 2-arylacetophenone derivative (2) as the starting material can be prepared, for example, by a known process (YAKUGAKU ZASSHI, 74, 495-497, 1954).
The reaction between the compound (2) and the haloacetate ester can be conducted in the presence of a base in a solvent. Potassium tert-butoxide, lithium diisopropylamide (LDA) or the like can be mentioned as a base usable here, and tetrahydrofuran or the like can be mentioned as a solvent usable here. The reaction is brought to completion at xe2x88x9220 to 40xc2x0 C. in 1 to 10 hours, preferably at xe2x88x925 to 25xc2x0 C. in 2 to 5 hours.
Further, the reaction between the resultant compound (3) and hydrazine hydrate can be conducted in a solvent, and anhydrous hydrazine may be used in place of hydrazine hydrate. As the solvent, a lower alcohol such as ethanol, methanol, n-propanol or isopropanol, tetrahydrofuran, 1,4-dioxane or the like can be used. The reaction is brought to completion at 50 to 150xc2x0 C. in 5 to 50 hours, preferably at 80 to 100xc2x0 C. in 10 to 30 hours.
(2) Preparation of 4,5-dihydro-2H-pyridazin-3-one derivatives (1d: in the formula (1), a single bond is formed between the 4-position and the 5-position, and X is an oxygen atom.):
A 2-substituted 4,5-dihydro-2H-pyridazin-3-one derivative (1d) can be obtained by reacting a compound, which is represented by the formula:
R3xe2x80x94Axe2x80x94NHNH2.2HCl
wherein R3 and A have the same meanings as defined above, with the compound (3) in the presence of sodium acetate in a solvent.
As a solvent usable in this reaction, methanol, ethanol, n-propanol, isopropanol, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane or the like can be mentioned. A lower alcohol or a water-containing lower alcohol is particularly preferred. The reaction is brought to completion at 40 to 150xc2x0 C. in 1 to 80 hours, preferably at 50 to 120xc2x0 C. in 5 to 50 hours.
(3) Preparation of 2H-pyridazin-3-one derivatives (1b: in the formula (1), A is a single bond, R3 is a hydrogen atom, X is an oxygen atom, and a double bond is formed between the 4-position and the 5-position):
(i) Preparation by a dehydrogenating reaction:
A 2H-pyridazin-3-one derivative (1b) can be obtained by reacting a dehydrogenating agent with the compound (1a) in acetic acid.
As the dehydrogenating agent, bromine, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or the like can be used. As the solvent, acetic acid or the like is usable. The reaction is brought to completion at 30 to 150xc2x0 C. in 5 to 50 hours, preferably at 50 to 120xc2x0 C. in 10 to 30 hours.
(ii) Preparation by a dehydrating reaction:
A 2H-pyridazin-3-one derivative (1b) can be obtained by reacting glyoxalic acidxe2x80x94which has been formed by causing sodium periodate to act on tartaric acid under acidic conditionsxe2x80x94with the 2-arylacetophenone derivative (2) under basic conditions, reacting hydrazine hydrate with the resultant 2-hydroxy-4-oxobutanoic acid derivative (4) in a lower alcohol as a solvent to convert it into a 4,5-dihydro-4-hydroxy-2H-pyridazin-3-one derivative (5), and then subjecting the derivative (5) to a dehydrating reaction in a solvent while using para-toluenesulfonic acid hydrate as a catalyst.
In the reaction between the compound (2) and glyoxalic acid, commercially-available glyoxalic acid hydrate can also be used in place of glyoxalic acid formed by causing sodium periodate to act on tartaric acid. As an acid usable upon formation of glyoxalic acid, an inorganic acid such as sulfuric acid, hydrochloric acid or phosphoric acid can be mentioned. As a base usable in the reaction between the compound (2) and glyoxalic acid, an inorganic base such as caustic soda or caustic potash or an organic base such as benzyltrimethylammonium hydroxide (Triton B) can be mentioned. In these reactions, the synthesis step of glyoxalic acid is brought to completion generally at xe2x88x9215 to 30C in 20 to 180 minutes, preferably around 0 to 25xc2x0 C. in 30 to 60 minutes. The reaction with the compound (2) is conducted preferably at 0 to 120xc2x0 C., and is brought to completion by reacting them, preferably at room temperature for 10 to 25 hours and then at 70xc2x0 C. for 0.5 to 2 hours. As the solvent, a lower alcohol such as ethanol, methanol, n-propanol or iso-propanol, tetrahydrofuran, 1,4-dioxane or the like can be used. Concerning the reaction between the compound (4) and hydrazine hydrate, anhydrous hydrazine can also be used in place of hydrazine hydrate. The reaction is brought to completion at 50 to 150xc2x0 C. in 5 to 30 hours, preferably at 80 to 100xc2x0 C. in 10 to 20 hours. As the solvent, a lower alcohol such as ethanol, methanol, n-propanol or isopropanol, tetrahydrofuran, 1,4-dioxane or the like can be used. In the dehydrating reaction of the compound (5), para-toluenesulfonic acid hydrate or the like can be used as a catalyst. As the solvent, toluene, benzene or the like can be used. The reaction is brought to completion at 50 to 150xc2x0 C. in 3 to 50 hours, preferably at 80 to 130xc2x0 C. in 5 to 30 hours.
(4) Preparation of 2H-pyridazin-3-one derivatives (1c: in the formula (1), X is an oxygen atom, and a double bond is formed between the 4-position and the 5-position.):
(i) Preparation of the compound (1c) from the compound (1b):
(a) Preparation by a reaction between (1b) and a halide or reactive ester: 2-Substituted 2H-pyridazin-3-one derivatives of a certain type (1c) can each be obtained by reacting a compound, which is represented by the following formula:
R3xe2x80x94Axe2x80x94Y
wherein R3 and A have the same meanings as defined above and Y represents a halogen atom or an OH group already converted into a reactive ester group, with the compound (1b) in the presence of a base in a solvent.
As a base usable in this reaction, an inorganic base such as potassium carbonate or sodium carbonate or an organic base such as a metal alkoxide can be mentioned. As the solvent, N,N-dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone or the like can be used. The reaction is brought to completion at 20 to 150xc2x0 C. in 1 to 20 hours, preferably at 50 to 130xc2x0 C. in 2 to 10 hours.
Each compound (1c) in which the 2-substituent is a piperidylalkyl group can be prepared by protecting the nitrogen atom of the piperidyl alkanol as the starting material, converting the hydroxyl group into a reactive ester group, reacting the compound (1b) with the resultant compound, and then conducting deprotection. Further, its N-lower alkylation makes it possible to prepare an N-(lower alkyl)piperidylalkyl derivative.
As a protecting group for the nitrogen atom of the piperidyl alkanol, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a dimethylphosphinothioyl group or the like is preferred. The compound protected by such a group can be obtained by reacting di-tert-butyl carbonate, benzyloxycarbonyl chloride or the like with the piperidyl alkanol in the presence of a base such as triethylamine or 4-dimethylaminopyridiene. As a solvent, tetrahydrofuran, diethyl ether, ethyl acetate, methylene chloride, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethanol, iso-propanol or the like can be used. The reaction is brought to completion at xe2x88x9215 to 50xc2x0 C. in 5 to 50 hours, preferably at xe2x88x920 to 20xc2x0 C. in 1 to 30 hours.
As the reactive ester group of the hydroxyl group, a tosyloxy group, a mesyloxy group, a benzenesulfonyloxy group or the like is preferred. A compound which contains such a group can be obtained by reacting para-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, benzenesulfonyl chloride or the like with the N-protected piperidyl alkanol in the presence of a base such as pyridine, triethylamine or collidine. As a solvent, pyridine, tetrahydrofuran, diethyl ether, ethyl acetate, methylene chloride, chloroform, N,N-dimethylformamide, dimethyl sulfoxide or the like can be used. The reaction is brought to completion at xe2x88x9215 to 50xc2x0 C. in 1 to 50 hours, preferably at xe2x88x925 to 30xc2x0 C. in 1 to 10 hours.
The reaction between the compound (1b) and the reactive ester derivative of the N-protected piperidyl alkanol can be conducted in the presence of a base in a solvent. As a base usable here, an inorganic base such as potassium carbonate or sodium carbonate or an organic base such as a metal alkoxide can be mentioned. As a solvent, N,N-dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone or the like can be used. The reaction is brought to completion at 20 to 150xc2x0 C. in 1 to 30 hours, preferably at 50 to 130xc2x0 C. in 2 to 10 hours.
The deprotection of the protecting group on the nitrogen atom of the piperidyl group can be effected by heating the N-protected piperidyl alkanol in the presence of an acid catalyst in a solvent. As an acid usable here, hydrochloric acid, sulfuric acid, acetic acid or the like can be mentioned. Such an acid may be in a form diluted with water. Preferred is 2 to 10 N hydrochloric acid, with 4 to 8 N hydrochloric acid being particularly preferred. As the solvent, tetrahydrofuran, methanol, ethanol, isopropanol, N,N-dimethylformamide or the like can be used. The reaction is brought to completion at 40 to 150xc2x0 C. in 0.5 to 10 hours, preferably at 50 to 130xc2x0 C. in 2 to 5 hours.
The N-lower alkylation of the thus-deprotected piperidylalkyl derivative can be conducted by reacting a lower alkyl sulfate, a lower alkyl halide or the like in the presence of a base in a solvent. As a base usable here, sodium hydrogencarbonate, potassium carbonate or the like can be mentioned. As the solvent, acetone, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, a mixed solvent thereof or the like is preferred. The reaction is brought to completion at 20 to 150xc2x0 C. in 0.5 to 10 hours, preferably at 50 to 130xc2x0 C. in 1 to 5 hours.
(b) Preparation via a 2-hydroxyalkyl derivative:
A compound (1c) the 2-substituent of which is a piperidinoalkyl, piperazinoalkyl or morpholinoalkyl group can be prepared by converting the hydroxyl group of the 2-hydroxyalkyl derivative, which has been obtained by reacting an alkylene chlorohydrin or alkylene carbonate with the compound (1b), into a reactive ester group and then reacting a corresponding amine.
The synthesis of the 2-hydroxyalkyl derivative can be conducted by reacting the compound (1b) with an alkylene chlorohydrin in the presence of a base, for example, in a known manner [Eur. J. Med. Chem. Chim. Ther., 14(1), 53-60, 1979] or by heating the compound (1b) and the alkylene carbonate in the presence or absence of a quaternary ammonium salt as a catalyst in a solvent. As a quaternary ammonium salt usable here, tetraethylammonium iodide, tetraethylammonium bromide, tetra(n-butyl)ammonium iodide, tetra(n-butyl)ammonium bromide or the like can be mentioned. As the solvent, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or the like can be mentioned. The reaction is brought to completion at 80 to 180xc2x0 C. in 0.5 to 10 hours, preferably at 120 to 160xc2x0 C. in 1 to 5 hours.
As the reactive ester group of the hydroxyl group, a tosyloxy group, a mesyloxy group, a benzenesulfonyloxy group or the like is preferred. A compound having such a group can be obtained by reacting paratoluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, benzenesulfonyl chloride or the like with the hydroxylalkyl derivative in the presence of a base such as pyridine, triethylamine or collidine. As a solvent, pyridine, terahydrofuran, diethyl ether, ethyl acetate, methylene chloride, chloroform, N,N-dimethylformamide, dimethylsulfoxide or the like can be used. The reaction is brought to completion at xe2x88x9215 to 50xc2x0 C. in 1 to 50 hours, preferably at xe2x88x925 to 30xc2x0 C. in 1 to 10 hours.
The reaction between the reactive ester derivative and the amine can be conducted by heating the reactive ester derivative in the presence of an excess amount of the amine in a solvent or in a solventless manner or reacting the amine in the presence of an organic amine such as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or the like or an inorganic base such as potassium carbonate or sodium carbonate. As the solvent, dimethyl sulfoxide, pyridine, chloroform, methylene chloride, toluene, benzene or the like can be used besides N,N-dimethylformamide. The reaction is brought to completion at 0 to 150xc2x0 C. in 1 to 10 hours, preferably at 50 to 130xc2x0 C. in 1 to 5 hours.
(c) Preparation via a 2-carboxyalkyl derivative:
A compound (1c) the 2-substituent of which is an aminocarbonylalkyl group can be prepared by reacting a haloalkyl carboxylate with the compound (1b), hydrolyzing the ester group of the resultant 2-alkyl carboxylate ester derivative, converting it into a reactive acyl derivative, and then reacting it with a corresponding amine or condensing the carboxylic acid derivative and a corresponding amine with a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC).
As a base usable in the reaction between the compound (1b) and the haloalkyl carboxylate, an inorganic base such as potassium carbonate or sodium carbonate or an organic base such as Triton B can be mentioned. As a solvent, N,N-dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone or the like can be used. The reaction is brought to completion at 20 to 150xc2x0 C. in 1 to 30 hours, preferably at 50 to 120xc2x0 C. in 2 to 20 hours.
The hydrolyzing reaction of the ester group can be conducted by treating the ester derivative in the presence of a base such as caustic soda or caustic potash in a conventional manner.
As the reactive derivative of the carboxylic acid, an acid halide, a mixed acid anhydride or the like can be mentioned. The acid halide can be prepared with oxalyl chloride, thionyl chloride, thionyl bromide or the like, while the mixed acid anhydride can be synthesized with acetic anhydride, pivalic anhydride, methanesulfonic anhydride, para-toluenesulfonyl chloride or the like.
The reaction between these reactive ester derivative and amine can be conducted by reacting the reactive ester derivative with an excess amount of the amine in a solvent or in a solventless manner or by reacting the amine in the presence of an organic amine such as pyridine, triethylamine or DBU or an inorganic base such as potassium carbonate or sodium carbonate. As the solvent, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, chloroform, methylene chloride, toluene, benzene or the like can be used. The reaction is brought to completion at 0 to 150xc2x0 C. in 1 to 10 hours, preferably at 50 to 130xc2x0 C. in 1 to 5 hours.
(d) Preparation by other processes:
Among 2-substituted derivatives (1c), each derivative in which R3 is an aminophenyl group can be obtained by reducing the nitro group of a compound in which R3 is a nitrophenyl group, and its N-lower alkylation makes it possible to prepare an N-(lower alkyl)aminophenyl compound.
The reduction of the nitro group can be effected by conducting hydrogenation in an inert solvent such as ethyl acetate or ethanol while using palladium on charcoal or Raney nickel as a catalyst.
The thus-reduced product can be N-lower alkylated by reacting it with a lower alkyl sulfate, a lower alkyl halide or the like in the presence of a base in a solvent. The resulting N-monoalkyl and dialkyl derivatives can be isolated, respectively, from their mixture.
As the base employed in the N-lower alkylating reaction, sodium hydrogencarbonate, potassium carbonate, pyridine, triethylamine or the like can be mentioned. As the solvent, acetone, dimethyl sulfoxide, N,N-dimethylformamide or tetrahydrofuran, a mixed solvent of two or more of these solvents, or the like is preferred. The reaction is brought to completion at 20 to 150xc2x0 C. in 0.5 to 10 hours, preferably at 50 to 130xc2x0 C. in 1 to 5 hours.
(ii) Preparation of the compound (1c) from the compound (1d):
Using the compound (1d) as a starting material, the compound (1c) can be prepared in a similar manner as in the preparation of the compound (1b) from the compound (1a).
(iii) Preparation of compounds (1c) in each of which R1 or R2 is a lower alkylsulfinylphenyl group:
Among the compounds (1c), each derivative in which R1 or R2 is a lower alkylsulfinylphenyl group can be prepared by selectively oxidizing a derivative (1c) in which R1 or R2 is a lower alkylthiophenyl group.
The selective oxidizing reaction can be conducted using metha-chloroperbenzoic acid, hydrogen peroxide solution or the like as an oxidizing agent. The reaction is brought to completion at xe2x88x9230 to 30xc2x0 C. in 10 minutes to 10 hours, preferably at xe2x88x9210 to 10xc2x0 C. in 30 minutes to 1 hour. As a solvent, methylene chloride, chloroform or the like can be used.
(iv) Preparation of compounds (1c) in each of which R1 or R2 is a lower alkylsulfonylphenyl group:
Among the compounds (1c), each derivative in which R1 or R2 is a lower alkylsulfonylphenyl group can be prepared by oxidizing a derivative (1c) in which R1 or R2 is a lower alkylthiophenyl group.
The oxidizing reaction can be conducted using osmium tetraoxide-sodium periodate, metha-chloroperbenzoic acid or the like as an oxidizing agent. The reaction is brought to completion at xe2x88x9230 to 50xc2x0 C. in 1 to 24 hours, preferably at 0 to 20xc2x0 C. in 5 to 10 hours. As a solvent, acetone-water-chloroform or the like can be used.
(5) Preparation of 2H-pyridazin-3-thione derivatives (1e: in the formula (1), X is a sulfur atom, and a double bond is formed between the 4-position and the 5-position.):
Each 2H-pyridazine-3-thione derivative (1e) can be obtained by thioketonizing its corresponding 2H-pyridazin-3-one derivative with Lawesson""s reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) in a solvent.
It is preferred to use Lawesson""s reagent in 0.5 to 3 equivalents, notably 1 to 1.5 equivalents relative to the 2H-pyridazin-3-one derivative. The reaction is brought to completion at 30 to 150xc2x0 C. in 1 to 10 hours, preferably at 50 to 100xc2x0 C. in 2 to 8 hours. As a usable solvent, toluene, xylene or the like can be mentioned.
The intermediates and target compounds obtained in the above-described individual reactions can be separated and purified by purification methods commonly employed in organic synthesis chemistry, for example, by subjecting them to filtration, extraction, washing, drying, concentration, recrystallization, various chromatographic treatment, and the like. The intermediates may be provided for the next reactions without purifying them specifically. Further, they may also be obtained as solvates of solvents such as reaction solvents or recrystallization solvents, especially as hydrates.
The pyridazine derivatives (1) and their salts according to the present invention, which are available as described above, have excellent inhibitory activity against interleukin-1xcex2 production, and are useful for the prevention and treatment of diseases caused by stimulation of interleukin-1xcex2 production, for example, immune system diseases, inflammatory diseases, ischemic diseases, osteoporosis, ichorrhemia and the like, especially as medicines such as preventives and therapeutics for rheumatism, immune deficiency syndrome, arthritis, inflammatory colitis, ischemic heart diseases, ischemic encephalopathy, ischemic nephritis, ischemic hepatitis, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson""s disease, Alzheimer""s disease, leukemia and the like or as interleukin-1xcex2 production inhibitors.
Medicines according to the present invention contain the pyridazine derivatives (1) or their salts as effective ingredients. Their administration routes can include, for example, oral administration by tablets, capsules, granules, powders, syrups or the like and parenteral administration by intravenous injections, intramuscular injections, suppositories, inhalants, transdermal preparations, eye drops, nasal drops or the like. Upon formulation of pharmaceutical compositions of these various unit dosage forms, pharmaceutically acceptable carriers can be mixed with these effective ingredients. As such carriers, excipients, binders, extenders, disintegrators, surfactants, lubricants, dispersants, buffers, preservatives, corrigents, perfumes, coating agents, vehicles, diluents and the like can be used by combining them as desired.
The dosage of each medicine according to the present invention varies depending on the age, body weight, conditions, administration form, administration frequency and the like. In general, however, it is preferred to orally or parenterally administer to an adult the effective ingredient in an amount of about 0.01 to 1,000 mg, preferably 0.1 to 100 mg per day at once or in several portions.